tbuckley/cabot-search huggingface dataset:
Abstract 2644: BL-M02D1, a novel Trop2-targeting ADC, demonstrates robust anti-tumor efficacy in preclinical evaluation
Authors: Yong Zhang, Weili Wan, Shi Zhuo, Lan Chen, Gangrui Li, Shuwen Zhao, Jahan Salar Khalili, Sa Xiao, Yongqi Yan, Xuejiao Shen, Yi Zhu
Journal: Cancer Research (2023)

Abstract Trop2, also known as trophoblast antigen 2, is a transmembrane glycoprotein. It is therapeutically targeted in cancer due to its over-expression in a variety of human carcinomas. To develop a promising therapeutic anti-tumor agent, we generated BL-M02D1, an anti-Trop2-Ed-04 ADC. It is comprised of a novel monoclonal antibody against Trop2 (hu4D3), a cathepsin B cleavable linker, and a novel topoisomerase I inhibitor agent (Ed-04). The novel Ed-04 is a derivative of the alkaloid camptothecin and mediates cell cycle arrest at the S phase and subsequent apoptosis. BL-M02D1 achieves a high drug-to-antibody-ratio (DAR=8) with a highly stable linker. The antitumor efficacy of BL-M02D1 was evaluated in comparison to a commercialized Trop2-targeting ADC, IMMU-132, in xenograft tumor models. BL-M02D1 exhibited stronger tumor inhibition capacity than IMMU-132 at lower doses in the gastric cancer cell line NCI-N87, the breast cancer cell line MDA-MB-231, and the non-small cell lung cancer cell line HCC827 xenograft models. BL-M02D1 exhibited potent bystander effects, exemplified by strong tumor inhibition in a heterogeneous xenograft model of Trop2-positive and Trop2-negative tumor cells (A431 and SW620). This characteristic of BL-M02D1 was also compared to IMMU-132. In the heterogeneous Trop2 xenograft model (A431 and SW620), BL-M02D1 exhibited higher tumor inhibition capacity than IMMU-132, indicating that BL-M02D1 possess a more potent bystander effect than IMMU-132. In summary, these studies suggest BL-M02D1, a novel Trop2-targeting ADC, is potentially more efficacious in the treatment of Trop2-expressing carcinomas than IMMU-132. The clinical phase I has been progressing and the available data exhibit excellent efficacy in breast cancer therapy with manageable toxicity. Citation Format: Yong Zhang, Weili Wan, Shi Zhuo, Lan Chen, Gangrui Li, Shuwen Zhao, Jahan Salar Khalili, Sa Xiao, Yongqi Yan, Xuejiao Shen, Yi Zhu. BL-M02D1, a novel Trop2-targeting ADC, demonstrates robust anti-tumor efficacy in preclinical evaluation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2644.
Abstract 2625: KRAS activity-mediated mechanism of castration-resistant prostate cancer progression
Authors: Taiki Kamijima, Kouji Izumi, Yoshifumi Kadono, Atsushi Mizokami
Journal: Cancer Research (2023)

Abstract Purpose: Prostate cancer is highly androgen-dependent, and androgen receptor (AR) signaling is suppressed by treatment. However, there are cases in which disease progresses rapidly at the end of treatment even after AR suppression, suggesting that the disease progresses by mechanisms different from AR. The aim of this study is to investigate the KRAS signaling pathway as one of the mechanisms. Methods: We used the hormone-sensitive prostate cancer (HSPC) cell line LNCaP and the castration-resistant prostate cancer (CRPC) cell line DU145. We performed KRAS knockdown by si-RNA and activation of KRAS signaling by EGF stimulation. To examine KRAS signaling, PCR and Western blotting were performed. The changes in proliferation and migration due to inhibition and activation of KRAS signaling were confirmed. Results: RT-PCR showed a fusion gene of ubiquitin-conjugating enzyme UBE2L3 and KRAS (UBE2L3-KRAS) in DU145. Western blotting showed increased phosphorylation of ERK and p38 downstream of KRAS in DU145. KRAS knockdown inhibited proliferation and migration in DU145 but not in LNCaP. In EGF-stimulated activation of KRAS signaling, Western blotting showed activation of downstream KRAS signaling in LNCaP, but no change in proliferation and migration in fetal bovine serum (FBS)-added medium. In contrast, EGF stimulation of DU145 further activated downstream KRAS signaling and promoted proliferation and migration. The AR-dependent LNCaP showed almost no effect of KRAS signaling activation on cancer progression, whereas DU145 showed that KRAS signaling is involved in cancer progression. Conclusion: While HSPC is highly AR-dependent and does not show any effect of KRAS on cancer progression, KRAS may be involved in cancer progression in some CRPCs. Citation Format: Taiki Kamijima, Kouji Izumi, Yoshifumi Kadono, Atsushi Mizokami. KRAS activity-mediated mechanism of castration-resistant prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2625.
Abstract 4334: Clever-1/PD-L1 ratio predicts response to Bexmarilimab, a novel macrophage-guided immunotherapy, in immune deprived cancers
Authors: Mari L. Björkman, Elisa M. Vuorinen, Juho Jalkanen, Marie-Louise Fjällskog, Jussi Koivunen, Teppo Huttunen, Maija Hollmén, Petri Bono
Journal: Cancer Research (2023)

Abstract Introduction: Clever-1 is an immunosuppressive scavenger receptor expressed on tumor associated macrophages. High levels of Clever-1 are associated with poor survival, T-cell exclusion and dysfunction, and immunotherapy resistance. Bexmarilimab (FP-1305) is a novel humanized anti-Clever-1 IgG4-antibody capable of promoting an immune switch, potentially leading to intratumoral proinflammatory responses in patients. In a first-in-human all-comer single agent Phase I/II study in advanced solid tumors (NCT03733990) approximately 30% of patients in hepatocellular carcinoma, cutaneous melanoma and cholangiocarcinoma achieved immune activation, characterized by an IFNg response, which led to a survival benefit (ASCO 2022). Here, we show that patients getting a therapy benefit have immunologically cold tumors with low PD-L1 staining and high Clever-1 staining. Methods: Pre-treatment tumor samples were immunohistochemically stained for Clever-1 (4G9, Santa Cruz) using Ventana platform and scored by % of intratumoral positive cells out of all viable cells and PD-L1 (22C3, Agilent) with combined positivity scoring (CPS). Ratio (PD-L1/Clever-1) at baseline was compared using non-parametric Wilcoxon-test according to clinical benefit. Results: 23 successful baseline biopsies and stainings were obtained, 6 per cutaneous melanoma, 11 per cholangiocarcinoma and 1 per hepatocellular carcinoma, from patients treated with bexmarilimab. Patients had received an average of three previous lines of therapy. At baseline, patients that saw a clinical benefit (CBR) from bexmarilimab had average PD-L1/Clever-1 ratio of 0.2 compared to 4.4 (p=0.042, Wilcoxon nonparametric test) in patients that did not respond to the treatment. Conclusion: PD-L1/Clever-1 IHC staining ratio may be used to predict bexmarilimab responding patients. These patients have a low PD-L1 staining and low IFNg levels as reported previously, and are often refractory to checkpoint inhibitors and other T cell activating agents. Bexmarilimab provides a novel therapy option for a tumor group that is otherwise poorly responsive to immune therapies. Citation Format: Mari L. Björkman, Elisa M. Vuorinen, Juho Jalkanen, Marie-Louise Fjällskog, Jussi Koivunen, Teppo Huttunen, Maija Hollmén, Petri Bono. Clever-1/PD-L1 ratio predicts response to Bexmarilimab, a novel macrophage-guided immunotherapy, in immune deprived cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4334.
Abstract 1383: Mechanisms of ATG9 mediated aggrephagy initiation
Authors: Deshan Madhusanka, Colton McEwan, David Broadbent, Jens Schmidt, Joshua Andersen
Journal: Cancer Research (2023)

Abstract Highly biosynthetic cancer cells produce proteins at a rate that may exceed the capacity of protein folding machinery, resulting in an accumulation of misfolded proteins that are poly-ubiquitinated and clustered into phase-separated ‘ubiquitin-rich’ condensates. These condensates are the initiation point for a form of autophagy called aggrephagy, which maintains cancer cell homeostasis by degrading the misfolded protein condensates via the lysosome. Aggrephagy is a cancer cell vulnerability, yet its mechanisms are poorly understood, particularly the mechanisms by which autophagy machinery recognizes the ubiquitin-rich condensates to initiate aggrephagy. Among 15 core autophagy proteins, ATG9A is the only multi-pass transmembrane protein and is essential for all known forms of autophagy. Recent evidence indicates that ATG9A is a lipid scramblase, in complex with ATG2A, that channels lipids to a growing autophagosome, which ultimately engulfs the ubiquitin-rich condensate. However, the mechanism of ATG9A recruitment to these condensates is not understood. Our data indicate that genetic or chemical manipulations of cells that cause ubiquitin-rich condensates to accumulate causing a corresponding accumulation of ATG9A. Furthermore, the induction of artificial ubiquitin-rich condensates, composed of chains of M1-linked ubiquitin, is sufficient to recruit ATG9A. Using a CRISPR knockout and reconstitution approach, we show that ATG9A is essential for assembling other autophagy machinery at ubiquitin-rich condensates. Together, our data support a model in which ATG9A recruitment is the initiating step for aggrephagy. Furthermore, our data suggest a signal or molecular pattern within the condensate promotes ATG9A recruitment to initiate aggrephagy. Our current work focuses on identifying features of ATG9A and components of the ubiquitin-rich condensate that cooperate to recruit ATG9A to these sites of aggrephagy initiation. Citation Format: Deshan Madhusanka, Colton McEwan, David Broadbent, Jens Schmidt, Joshua Andersen. Mechanisms of ATG9 mediated aggrephagy initiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1383.
Abstract 3923: Identification of membrane-expressed CAPRIN-1 as a novel and universal cancer target and generation of a therapeutic anti-CAPRIN-1 antibody TRK-950
Authors: Fumiyoshi Okano, Takanori Saito, Yoshitaka Minamida, Shinichi Kobayashi, Takayoshi Ido, Yasushi Miyauchi, Ukei Wasai, Jiang Ke, Alexandra Aicher, Christopher Heeschen, Tetsu Yonehara
Journal: Cancer Research (2023)

Abstract Specific targets for cancer treatment are highly desirable, but still remain to be discovered. While previous reports suggested that CAPRIN-1 localizes in the cytoplasm, here we now show that part of this molecule is strongly expressed on the cell membrane surface in most solid cancers, but not normal tissues. Notably, the membrane expression of CAPRIN-1 extended to the subset of highly tumorigenic cancer stem cells and EMT induced metastatic cancer cells. In addition, we revealed that cancer cells with particularly high CAPRIN-1 surface expression exhibited enhanced tumorigenicity. We generated a therapeutic humanized anti-CAPRIN-1 antibody (TRK-950), which strongly and specifically binds to various cancer cells and shows anti-tumor effects via engagement of immune cells. TRK-950 was further developed as a new cancer drug and a series of pre-clinical studies demonstrates its therapeutic potency in a tumor bearing mouse model and safety in a relevant cynomolgus monkey model. Together our data demonstrate that CAPRIN-1 is a novel and universal target for cancer therapies. A phase I clinical study of TRK-950 (NCT02990481) has been completed and a phase Ib study (combination with approved drugs) is currently underway (NCT03872947). Citation Format: Fumiyoshi Okano, Takanori Saito, Yoshitaka Minamida, Shinichi Kobayashi, Takayoshi Ido, Yasushi Miyauchi, Ukei Wasai, Jiang Ke, Alexandra Aicher, Christopher Heeschen, Tetsu Yonehara. Identification of membrane-expressed CAPRIN-1 as a novel and universal cancer target and generation of a therapeutic anti-CAPRIN-1 antibody TRK-950. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3923.
Abstract 2648: In vivo efficacy and preclinical safety profile of NN3201, an anti-cKIT antibody-drug conjugate, for treating SCLC and AML
Authors: Han-Jik Ko, Sung Tae Kim, Jin Gu Cho, Jin-Ock Kim, Jung Tae Lee, Sang Gyu Park
Journal: Cancer Research (2023)

Abstract Overexpression and activating mutations of cKIT are associated with tumor aggressiveness and poor prognosis in various cancer patients such as small cell lung cancer (SCLC), gastrointestinal stromal tumor (GIST), acute myeloid leukemia (AML), and mastocytoma. Since small molecule inhibitors including imatinib frequently have a limited therapeutic application due to eventual drug resistance and severe adverse events, we developed the cKIT-directed antibody-drug conjugate (ADC), NN3201, for the treatment of wild-type and mutant cKIT-positive cancers. NN3201 is an ADC conjugate of the antimitotic payload MMAE to the fully human 2G4 antibody, directed against cKIT, via the cysteine re-bridging technology ThioBridge® at a drug-to-antibody ratio (DAR) of 4. NN3201 displayed preferable biophysical properties and broadly potent in vitro antitumor activities across various cKIT-positive tumor cell lines. NN3201 exhibited potent in vivo antitumor activities in cKIT-positive tumor cell line xenograft and patient-derived tumor xenograft models of SCLC and AML, representing robust and durable antitumor responses. Furthermore, in a single-dose toxicity study with cynomolgus monkey, no significant or severe clinical toxicity signs were observed in animals dosed at 1, 2, and 3 mg/kg. Even though a decrease in reticulocyte, red cell mass (hemoglobin and red blood cell), neutrophil, and monocyte counts, along with bone marrow recovery and reticulocyte compensatory mechanism, red blood cell and white blood cell recovery were observed from day 14 in the low and medium dose groups and day 21 in the high dose group, dose-dependently. These preclinical results suggest that NN3201 is a potential therapeutic agent for the treatment of cKIT-positive cancers and support the further clinical evaluation in SCLC and AML. Citation Format: Han-Jik Ko, Sung Tae Kim, Jin Gu Cho, Jin-Ock Kim, Jung Tae Lee, Sang Gyu Park. In vivo efficacy and preclinical safety profile of NN3201, an anti-cKIT antibody-drug conjugate, for treating SCLC and AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2648.
Abstract 1382: Expression and intracellular translocation of cancer biomarkers in hepatocarcinoma cells induced by changes in mitochondrial metabolism
Authors: Bradley R. Larson, Monika Gooz, Eduardo Maldonado
Journal: Cancer Research (2023)

Abstract Hepatocarcinoma is one of the most common cancer types in the U.S. with limited treatment options and poor survival rate. Recently, cancer bioenergetics emerged as a promising source of targets to develop novel anticancer agents. The identification of biomarkers is essential for screening and validation of small molecules proposed as chemotherapeutic agents. In this regard, there is a great need for high-throughput/high-content methods, which require short and reproducible sample preparation. In this project, we used the erastin-like compound X1 in the well-characterized SNU-449 hepatocarcinoma cell line. Erastin initially enhances mitochondrial function and ROS formation leading to subsequent mitochondrial dysfunction. As readout, we employed directly and indirectly labeled fluorescent antibodies to visualize and quantify expression of proliferative and antiproliferative markers Ki-67 and cytoskeleton-associated protein 4/p63 (CKAP4/p63), as well as expression and intracellular translocation of the tumor suppressor protein p53. Using the Agilent BioTek Cytation 5 cell imaging multimode reader and Agilent BioTek Gen5 microplate reader and imager software, we successfully validated these markers and the corresponding antibodies as tools to study long-term effects of xenobiotics on mitochondrial bioenergetics. The method allows for fast and reliable screening of potential drug candidates. Acknowledgement: This work was supported in part by the Chan Zuckerberg Initiative, Silicon Valley Community Foundation, and the NIH S10 OD028663 to M.G. and by the U.S. National Institutes of Health (NIH/NCI) R01 CA184456, and South Carolina Translational Research Pilot Project UL1 TR001450-SCTR to E.N.M. Citation Format: Bradley R. Larson, Monika Gooz, Eduardo Maldonado. Expression and intracellular translocation of cancer biomarkers in hepatocarcinoma cells induced by changes in mitochondrial metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1382.
Abstract 2642: BL-B01D1, a novel EGFR×HER3-targeting ADC, demonstrates robust anti-tumor efficacy in preclinical evaluation
Authors: Weili Wan, Shuwen Zhao, Shi Zhuo, Yong Zhang, Lan Chen, Gangrui Li, Blair Renshaw, Jahan Salar Khalili, Sa Xiao, Yi Zhu
Journal: Cancer Research (2023)

Abstract EGFR and HER3, members of the human epidermal growth factor receptor (ErbB) family, are targeted in cancer therapy due to their over-expression and pathway dependence in common human epithelial carcinoma tumors. To develop a promising therapeutic anti-tumor agent, we generated BL-B01D1, an EGFR×HER3-targeting ADC, which can bind to EGFR and/or HER3 positive cells and is expected to be superior to anti-EGFR and anti-HER3 ADCs. It is comprised of a bispecific antibody against EGFR/HER3 (SI-B001), a cathepsin B cleavable linker, and a novel topoisomerase I inhibitor agent (Ed-04), which is a derivative of the alkaloid camptothecin, driving cell cycle arrest at the S phase and subsequent apoptosis. BL-B01D1 achieves a high drug-to-antibody-ratio (DAR=8) with a highly stable linker. The pharmacological potential of this ADC was evaluated in comparison to its parental single antigen-targeting ADCs in xenograft models composed of either the human colorectal cancer cell line SW620 or pancreatic cancer cell line BxPC3. The tumor inhibition activity of BL-B01D1 was compared with ADCs prepared from each parental anti-EGFR or anti-HER3 mAb conjugated with the same linker and payload. The bispecific ADC, BL-B01D1 exhibited stronger tumor inhibition capacity than the anti-EGFR ADC and the anti-HER3 ADC separately. The preclinical studies suggest BL-B01D1, as an EGFR×HER3-targeting ADC, might be a promising novel agent with activity toward a broad range of human cancers. The clinical phase I has been progressing and the available data exhibit excellent efficacy but low levels of targeted toxicity in the non-small cell lung cancer (NSCLC) treatment setting. Overall, these data suggest BL-B01D1 has potential to serve as a novel, efficacious therapeutic agent for NSCLC with similar therapeutic impact as DS-8201 has in breast cancer treatment. Citation Format: Weili Wan, Shuwen Zhao, Shi Zhuo, Yong Zhang, Lan Chen, Gangrui Li, Blair Renshaw, Jahan Salar Khalili, Sa Xiao, Yi Zhu. BL-B01D1, a novel EGFR×HER3-targeting ADC, demonstrates robust anti-tumor efficacy in preclinical evaluation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2642.
Metal‐based nanomaterials and nanocomposites as promising frontier in cancer chemotherapy
Authors: Sunil Kumar, Monu Kumar Shukla, Abhishek Kumar Sharma, Gururaj K. Jayaprakash, Rajiv K. Tonk, Dinesh K. Chellappan, Sachin Kumar Singh, Kamal Dua, Faheem Ahmed, Sanjib Bhattacharyya, Deepak Kumar
Journal: MedComm (2023)

Abstract Cancer is a disease associated with complex pathology and one of the most prevalent and leading reasons for mortality in the world. Current chemotherapy has challenges with cytotoxicity, selectivity, multidrug resistance, and the formation of stemlike cells. Nanomaterials (NMs) have unique properties that make them useful for various diagnostic and therapeutic purposes in cancer research. NMs can be engineered to target cancer cells for early detection and can deliver drugs directly to cancer cells, reducing side effects and improving treatment efficacy. Several of NMs can also be used for photothermal therapy to destroy cancer cells or enhance immune response to cancer by delivering immune‐stimulating molecules to immune cells or modulating the tumor microenvironment. NMs are being modified to overcome issues, such as toxicity, lack of selectivity, increase drug capacity, and bioavailability, for a wide spectrum of cancer therapies. To improve targeted drug delivery using nano‐carriers, noteworthy research is required. Several metal‐based NMs have been studied with the expectation of finding a cure for cancer treatment. In this review, the current development and the potential of plant and metal‐based NMs with their effects on size and shape have been discussed along with their more effective usage in cancer diagnosis and treatment.
Abstract 4246: Synergistic inhibition of prostate tumor growth and progression by the combination of curcumin and ursolic acid in HiMyc mice
Authors: Chelsea A. Friedman, Achinto Saha, John DiGiovanni
Journal: Cancer Research (2023)

Abstract Prostate cancer (PCa) is the second leading cause of cancer death among men in the United States. According to the World Health Organization, approximately one-third of all cancer deaths could be prevented through an increased consumption of natural compounds. Through the use of a two-tiered screening method in PCa cells (depletion of cellular ATP level followed by glutamine uptake) of a phytochemical library, curcumin and ursolic acid were selected for further investigation. Twenty-four hour treatment of LNCaP, 22Rv1 and HMVP2 cells with the combination resulted in significant decreases in expression of members of the miR-17-92 and miR-106b-25 clusters, which are upregulated in PCa and have been shown to be involved in tumorigenesis, cell survival, and metastasis. In the HiMyc mouse model, where mice spontaneously develop primary PCa, supplementing diets with the combination of curcumin (1%) and ursolic acid (0.2%) resulted in significant inhibition of tumor growth and progression compared to diets containing either compound alone. There were no differences in body weight or food consumption in any of the diet groups during the tumor experiment. The current data suggests that the combination of curcumin and ursolic acid synergistically inhibits PCa growth and progression in HiMyc mice, which may be in part due to their effects on microRNA expression. Ongoing studies are further examining the role of specific miRNAs as well as oncogenic signaling pathways potentially involved in the mechanism of synergistic chemopreventive action of this combination. The current data suggest that this novel combination could be a valuable therapeutic option for prevention and/or treatment of PCa. Funding: This work was supported by NIH Grant CA228404. Citation Format: Chelsea A. Friedman, Achinto Saha, John DiGiovanni. Synergistic inhibition of prostate tumor growth and progression by the combination of curcumin and ursolic acid in HiMyc mice. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4246.